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Having spent a good deal of time enjoying the company of their newfound family and friends at Witch Mountain and intensively studying and practicing their supernatural powers, Tony and his sister Tia are in need of a vacation. Uncle Bené drops them off in their flying saucer at the Rose Bowl stadium in Los Angeles, California, after which the siblings quickly become separated from each other. A man named Dr. Victor Gannon (Lee) and his assistant Letha Wedge (Davis) happen to see Tony using his powers to save their henchman from certain death. Realizing that Tony has supernatural powers, Dr. Gannon drugs the boy with a tranquilizer shot and takes him back to their laboratory. There, Dr. Gannon successfully tests a new mind-control technology on him. Under its influence, Tony is completely hypnotized and does everything that his kidnappers want him to do, like stealing gold from a museum exhibit and stopping Tia from finding them. With Tony at his robotic bidding, Dr. Gannon hopes to achieve recognition within the scientific community and worldwide power, while Letha merely wants a return on her investment.

Tia uses her telepathic powers to locate Tony. She gets additional help from a group of would-be toughs whom she comes across, called the Earthquake Gang, and a hapless truant officer Mr. Yokomoto — whom the toughs call "Yo-Yo" — to find her brother, and foil the villains' nefarious plans.

The otherwise vacant lot, upon which the children's dilapidated hideout mansion stands, was at the Alameda Street railroad yard, where the Rochester House (a relic from 1880's)[1] was waiting for restoration and relocation. The house was used as the hideout in the movie. The house however was never restored and ultimately demolished in 1979 (even though the link above places the house in Virginia, and says that it was listed as a historic building in 2002).

Scenes of Dr. Victor Gannon's mansion, the location of his laboratory, were filmed at Moby Castle on Durand Drive, Hollywood Hills, Los Angeles.

The gold-bar robbery sequence was filmed at the Natural History Museum in Exposition Park, Los Angeles. The building facing the Park's Rose Garden was used for exterior shots of the museum. The scene in which Yokomoto's van is overturned and breaks a fire-hydrant was filmed near the Sunset Boulevard bridge and Glendale Boulevard underpass intersection, in the Echo Park district.

Actors Kim Richards and Ike Eisenmann appear in at least four films together — this one, the original 1975 Disney film Escape to Witch Mountain, and the television film Devil Dog: The Hound of Hell. Richards portrays the roadside waitress and Eisenmann portrays the Sheriff in a re-imagined remake of the original film, Race to Witch Mountain, released in March 2009.

Jack Soo (Mr. "Yo-Yo" Yokomoto) was diagnosed with esophageal cancer in the Autumn of 1978, several months after the film's release. Return from Witch Mountain would be his final movie appearance, as he died the following January.

The emergency voice heard over Yokomoto's van radio — announcing the problem at the plutonium plant — is that of Gary Owens.